The purpose of this project is to determine the natural course of renal disease in type 2 diabetes mellitus in the Pima Indians and to identify the underlying pathogenetic mechanisms involved in the initiation and progression of renal disease in this type of diabetes. This project, in part, represents an extension of work previously reported as Project Number Z01 DK 69037. Glomerular function was measured over a 4-year period in 194 Pima Indians selected to represent stages in the development and progression of diabetic renal disease. Follow-up was extended for an additional 24 months in the 57 subjects with microalbuminuria to characterize the evolution and mechanisms of progressive diabetic glomerular injury. Subjects underwent serial determinations of albuminuria and GFR, and a subset of them underwent morphometric analysis of glomeruli in two biopsies separated by an interval of 48 months. GFR declined by 15% over 60-84 months, regardless of whether or not subjects progressed to macroalbuminuria. Baseline biopsy revealed no differences from duration-matched normoalbuminuric controls for filtration surface area, thickness of GBM, foot process width, fractional mesangial volume, or percent global sclerosis. Repeat biopsy after 48 months indicated that the declining GFR was associated with modest increases in the widths of the GBM and foot processes, changes that lowered hydraulic permeability by 15%. Filtration surface area declined by 20%. Together these changes led to a fall of 31% in single-nephron Kf. The modest decline in GFR over 5-7 years and the absence of significant glomerular pathology suggest that trials of renoprotective therapy in patients with type 2 diabetes and microalbuminuria will need to be long term. The effect of the intrauterine environment on the development of diabetic renal disease was also examined. Both intrauterine growth retardation and fetal exposure to maternal diabetes predicted diabetic nephropathy. These factors may contribute to the increasing incidence of diabetic nephropathy found in this population.